Spell Checking Nature: Versatility of CRISPR/Cas9 for Developing Treatments for Inherited Disorders

Am J Hum Genet. 2016 Jan 7;98(1):90-101. doi: 10.1016/j.ajhg.2015.11.012. Epub 2015 Dec 10.


Clustered regularly interspaced short palindromic repeat (CRISPR) has arisen as a frontrunner for efficient genome engineering. However, the potentially broad therapeutic implications are largely unexplored. Here, to investigate the therapeutic potential of CRISPR/Cas9 in a diverse set of genetic disorders, we establish a pipeline that uses readily obtainable cells from affected individuals. We show that an adapted version of CRISPR/Cas9 increases the amount of utrophin, a known disease modifier in Duchenne muscular dystrophy (DMD). Furthermore, we demonstrate preferential elimination of the dominant-negative FGFR3 c.1138G>A allele in fibroblasts of an individual affected by achondroplasia. Using a previously undescribed approach involving single guide RNA, we successfully removed large genome rearrangement in primary cells of an individual with an X chromosome duplication including MECP2. Moreover, removal of a duplication of DMD exons 18-30 in myotubes of an individual affected by DMD produced full-length dystrophin. Our findings establish the far-reaching therapeutic utility of CRISPR/Cas9, which can be tailored to target numerous inherited disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Clustered Regularly Interspaced Short Palindromic Repeats*
  • Gene Expression
  • Genetic Diseases, Inborn / genetics
  • Genetic Diseases, Inborn / therapy*
  • Humans
  • Muscular Dystrophy, Duchenne / genetics
  • Muscular Dystrophy, Duchenne / therapy